Effect of intracellular Ca2+ and action potential duration on L-type Ca2+ channel inactivation and recovery from inactivation in rabbit cardiac myocytes

Julio Altamirano, Donald M Bers

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

Ca2+ current (ICa) recovery from inactivation is necessary for normal cardiac excitation-contraction coupling. In normal hearts, increased stimulation frequency increases force, but in heart failure (HF) this force-frequency relationship (FFR) is often flattened or reversed. Although reduced sarcoplasmic reticulum Ca2+-ATPase function may be involved, decreased ICa availability may also contribute. Longer action potential duration (APD), slower intracellular Ca2+ concentration ([Ca2+]i) decline, and higher diastolic [Ca 2+]i in HF could all slow ICa recovery from inactivation, thereby decreasing ICa availability. We measured the effect of different diastolic [Ca2+]i on ICa inactivation and recovery from inactivation in rabbit cardiac myocytes. Both ICa and Ba2+ current (IBa) were measured. ICa decay was accelerated only at high diastolic [Ca 2+]i (600 nM). IBa inactivation was slower but insensitive to [Ca2+]i. Membrane potential dependence of ICa or IBa availability was not affected by [Ca 2+]i <600 nM. Recovery from inactivation was slowed by both depolarization and high [Ca2+]i. We also used perforated patch with action potential (AP)-clamp and normal Ca2+ transients, using various APDs as conditioning pulses for different frequencies (and to simulate HF APD). Recovery of ICa following longer APD was increasingly incomplete, decreasing ICa availability. Trains of long APs caused a larger ICa decrease than short APD at the same frequency. This effect on ICa availability was exacerbated by slowing twitch [Ca2+]i decline by ∼50%. We conclude that long APD and slower [Ca2+]i decline lead to cumulative inactivation limiting ICa at high heart rates and might contribute to the negative FFR in HF, independent of altered Ca2+ channel properties.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume293
Issue number1
DOIs
StatePublished - Jul 2007
Externally publishedYes

Keywords

  • Calcium ion buffers
  • Calcium ion current
  • Excitation-contraction coupling

ASJC Scopus subject areas

  • Physiology

Fingerprint Dive into the research topics of 'Effect of intracellular Ca<sup>2+</sup> and action potential duration on L-type Ca<sup>2+</sup> channel inactivation and recovery from inactivation in rabbit cardiac myocytes'. Together they form a unique fingerprint.

  • Cite this